Metabolite Regulation of the Insulin Receptor Family

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DESCRIPTION(adapted from applicant's abstract): Receptor tyrosine kinases initiate signal transduction along diverse pathways that are important for all aspects of life. The insulin receptor family has conserved structural features that make it unique among receptor tyrosines kinases, and should render it sensitive to the adenine nucleotide metabolite pool under physiological conditions. The insulin receptor (IR), insulin-like growth factor-1 receptor (IGF 1 R) and insulin receptor-related receptor (IRR) are heterotetrameric transmembrane proteins, in contrast to all other receptor tyrosine kinases which are monomeric. The unphosphorylated state of the insulin receptor is marked by a unique feature of its activation loop: there is intrasteric inhibition of the ATP and peptide binding sites. Relief of intrasteric inhibition by activation Loop autophosphorylation requires a conformational change induced by adenine nucleotide binding. To reconcile these unique features of the IR family with the broader understanding of protein kinase regulation, we will 1. Determine the contributions of specific conserved residues to intrasteric inhibition in the insulin receptor family. 2. Determine whether intrasteric inhibition and conformational sensitivity to ATP are conserved in human IGF 1 R and IRR. 3. Determine the conformation for basal-state autophosphorylation by X-ray crystallography. These studies will elucidate new properties of intrasteric inhibition and new regulatory features necessary for controlled receptor autophosphorylation. The long-term goals of this project will be to determine the functions these unique features may serve in development under conditions of environmental and metabolic stress, and their possible links to chronic degenerative conditions and insulin resistance in diabetes and obesity.